TinnitusContemporary theories of generation:

Pathophysiological correlatesAmr El Refaie

Tinnitus

• Why is it that complex?

• Tinnitus is a symptom, looking for a diagnosis

If it is a symptom?

• What are the causes?

• What is the pathogenesis?

• What are the effects? Bio-social model

So, If I am attending a patient with tinnitus

• What are the causes? Sinister pathology?

• How does it work? Can we affect the generation mechanisms?

• What are the effects? Can I improve the quality of life?

So, why should we investigate mechanisms of generation?

• We need to know the causes, if possible• Can we modify the symptom if we

understand the mechanism?• Can our search for a treatment be more

informed?

Plan of talk:

• Functional/system perspectives (Cochlear, cerebral perspectives)

• Neuronal/synaptic perspectives• Cellular/molecular perspectives

Auditory system perspective

The neurophysiological model

Auditory & Other Cortical AreasPerception & Evaluation (Consciousness, Memory, Attention)

AuditorySubconscious

Detection / Processing

Limbic SystemEmotions

Reactions

Auditory PeripherySource

Autonomic Nervous System

The Neuro-Physiological model

• Jastreboff and Hazell (1990)• A new Auditory signal received from the

cochlea is perceived and evaluated by sub-cortical and cortical centres

• The signal “ignition site” might be in the cochlea or the retrocochlear/Central regions

Ignition site

• Not that important?• The discordant damage theory• Correlation between traumatic agents

(noise, ototoxic drugs…) and injury to the OHCs and IHCs

• OHCs being damaged first and more severely affected in general

Ignition site

• A partially damaged basilar membrane will have areas with damaged OHCs and partially healthy IHCs

• Reduction or loss of hair cells results in abnormal activity in the afferent nerve fibres at frequencies around the focus of the lesion (edge effect, Jastreboff, 1990)

The discordant damage theory

• Afferent output from both OHCs and IHCs converge on the same group of neurones in the dorsal cochlear nucleus of the brain stem

• When the DCN receives excitation of the IHCs and not the OHCs, this creates an imbalance

The discordant damage theory

• The imbalance appear to create aberrant neural activity at certain level of the central auditory system

• Manifests itself as high frequency neuronal bursts (tinnitus)

• Damage to up to 30% OHCs might not demonstrate itself as hearing loss in audiogram, but still causes tinnitus (Jastreboff,2000)

The edge effect

• Tinnitus seem to develop close (around the edge) to the frequency region with the most hearing loss

• Implications for tinnitus measurements?• Implications for sound therapy?

Plasticity in central auditory system

• Plasticity first proposed by Ramon y Cajal

( 1852 - 1934 )

• Caused by

• Reorganization following an insult (sensory

deprivation as an example)

• Adaptation and change of functions

The role of sensory deprivation

• Tonotopic organization through the auditory system means that certain frequency areas on the basilar membrane supplies certain regions in the central auditory system with afferent signals

• Damage to the cochlea, resulting in SNHL will lead to loss of afferent information leaving this specific area (frequency region)

Sensory deprivation theory

• Corresponding areas in the central auditory system become starved (deprived) of sensory stimulation

• This might lead to:• Increased level of spontaneous activity• Plastic rearrangement of neurones leading to

abnormal firing patterns• This can be perceived as tinnitus

Applications

• Hearing aids as the first line of management in tinnitus accompanied by hearing loss

• The philosophy of “sound enrichment” instead of “masking noise”, or is it both?

Neuronal / synaptic perspectives

Synapse

• The connection between the axon of one neurone and the dendrites of another neurone

• It is a “functional connection”, as both neurones remain separate entities and only connected at the terminals (synaptic knobs)

Tinnitus and neuronal transmission

• There are evidences that some forms of tinnitus are related to hyperactivity at one or more areas of the auditory pathway

• Levels of hyperactivity ranges from the inferior colliculus (Eggermont, 2006) up to the auditory cortex (Schlee et al 2009)

Tinnitus and neuronal transmission

• Hyperactivity might be the result of:• - Increased synchronicity, as a result of injury

at the level of the cochlea/auditory nerve• - Injury, sensory deprivation, followed by

plastic reorganization at auditory neurones with erratic firing patterns

• Evidences of changes in tonotopic organizations by magnetoencephalogram (Muhlnickel 1998) and PET (Mirz et al 1999)

Suppression of neuronal hyperactivity

• ECT in the treatment of Schizophrenia and psychotic states

• The effect of cochlear implants switch on in patients with tinnitus and profound hearing loss

• Transtympanic electrical stimulation?

Transcranial magnetic stimulation (TMS)

• Alternation of cortical hyperactivity by the delivery of pulses of magnetic field through an external scalp coil

• A powerful current through the coil over a specific area in the scalp will create a secondary current, which penetrates the first few millimetres of the scalp and skull to affect brain tissue

Transcranial magnetic stimulation (TMS)

• Single session of high frequency repetitiveTMS (rTMS) over the temporal cortex

• Repeated sessions of low frequency rTMS over a period of time (more effective in suppression of chronic tinnitus)

Transcranial magnetic stimulation (TMS)

• Magnetic field affect neural depolarization and induce alteration in synaptic transmission

• Modulates thalamo-cortical dysrhythmia(cortical hyperactivity is believed to be related to loss of thalamic inhibition)

What we know so far

• Studies suggest that beneficial effects have been consistently demonstrated in several controlled studies (Langguth et al, 2009)

• High individual variability• There are still no high quality evidences

from the controlled studies, problems with sham stimulus, small numbers,..

What we don’t know:

• Probable side effects, even if the stimulation is localized, (it can’t be that localized!)

• Duration of improvement, long term results are not available

• The effect size of placebo

Direct electrical epidural stimulation

Direct electrical epidural stimulation

• Insertion of a permanent electrode epidurally

• Repetitive electrical stimulation• Invasive• Intractable tinnitus

The theory

• Tinnitus is related to reorganized hyperactivity of the auditory cortex

• This hyperactivity can be demonstrated by functional MRI and PET scan

• Tinnitus can be influenced by high frequency rTMS

• Electrode can be implanted for more efficient inhibition (De Ridder, 2004-2006)

Channelopathies• Several disorders of muscle membrane

excitability are linked to genetic mutations, controlling Calcium, Sodium and Chloride channels and acetylcholine receptors (Cannon, 1996)

• Ion channels are macromolecular proteins embedded in the cell wall, governing ion flow inside and outside of the cell, through either electrical gradient or concentration gradient

• Voltage-gated channels made of pore-forming subunits (alpha)

Channelopathies

• Genetic mutation• Autoimmune disorders• Toxicity• Iatrogenic

Channelopathies

• Epilepsy syndromes• Migraine• Cardiac arrhythmias• Muscular dystrophy• Periodic paralysis• Cystic fibrosis

Channelopathy

• Ca channelopathy:• Migraine, night blindness, episodic ataxia• Retinitis pigmentosa

• K channelopathy:• Syndromic hearing loss• Autosomal dominant non-syndromic SNHL

Channelopathy and the ear

• Mutations affecting the K channels in the OHCs and IHCs are known to be associated with non-syndromic autosomal dominant SNHL (Chromosome 14)

• Around 50 genes are implicated in non syndromal hearing loss

• The correlation between COCH gene, HL and Ca channelopathy

Tinnitus and the ionic channels

• Tinnitus as pain, a symptom for many diverse disorders

• Some forms of tinnitus, associated with known (Migraine) or suspected (Meniere’s) channelpathies might have ionic basis? Genetic studies?

Tinnitus and pharmacological treatment

• The effect of Nimodipine and L-calcium channel antagonists on some forms of tinnitus? (Davies et al, 1994)

• Lidocaine effect on tinnitus has been attributed to modulation of Sodium channels in the cochlea, as well ass its central effect, especially at the level of the inferior colliculus (Baguley, 2004)

Final thoughts (for now!)

• Tinnitus is a symptom, that can result from several diverse pathophysiological mechanisms

• What works for one kind of tinnitus, might not work for another

• Efforts must be done to understand the mechanism of an individual’s tinnitus

Final thoughts (for now)

• The individual account of a patient’s tinnitus

• Habituation of reaction• Habituation of perception• The role and make up of a tinnitus clinic

Thank you